Efficacy and safety of traditional Chinese medicine combined with western medicine for early-phase treatment of acute ischemic stroke based on the primary syndrome elements: protocol for a randomized controlled trial

Background and objective: Acute ischemic stroke is a major cause of disability among adults. Although traditional Chinese medicine and western medicine have been widely used for the treatment of acute ischemic stroke, their efficacy when used in combination for the treatment of acute ischemic stroke during the early phase is poorly understood. According to traditional Chinese medicine theory, the primary syndrome elements of acute ischemic stroke during the early stage include three pathogens, “wind,” “fire,” and “phlegm,” and treatments that target these primary syndrome elements contribute to recovery from the condition. We have designed a randomized controlled trial to investigate the efficacy and safety of traditional Chinese medicine combined with western medicine in the treatment of acute ischemic stroke during the early phase based on the primary syndrome elements. Subjects and methods: This prospective, single-center, assessor-blinded, randomized controlled trial will enroll 120 eligible patients with acute ischemic stroke who will receive treatment in the Department of Emergency, Dongfang Hospital of Beijing University of Chinese Medicine, China. Participants will be randomly assigned to a combined treatment group or a control group. Both groups will undergo treatment with conventional western medicine, and patients in the combined treatment group will also receive traditional Chinese medicine (i.e., oral stroke initial state decoction, intravenous Gastrodin injection, and Tanreqing injection; Xingnaojing injection will be added for patients who are unconscious). Immediately after admission, patients will undergo 3-day treatment for early-phase ischemic stroke and subsequently undergo a 2-week follow up. This study was approved by Hospital Ethics Committee, Dongfang Hospital, Beijing University of Traditional Medicine, China (approval No. JDF-IRB-2016033602) on November 2, 2016. Written informed consent will be obtained from conscious patients or the legal guardians of unconscious patients. Outcome measures: The primary outcome measures of this study are the National Institute of Health Stroke Scale score and traditional Chinese medicine stroke scale score on days 1, 3, 7, and 14 after treatment. Secondary outcome measures include National Institute of Health Stroke Scale score, Barthel index, Modified Rankin scale score, Glasgow coma scale score on days 1, 3, 7, and 14 after treatment, serum matrix metalloproteinase-9 and vascular endothelial growth factor levels on days 1 and 3 after treatment. Safety outcomes on days 1 and 3 after treatment and adverse events on days 3, 7, and 14 after treatment are also evaluated. Discussion: The results of this study will provide evidence to support the rationale for using traditional Chinese medicine combined with western medicine for the treatment of acute ischemic stroke during the early phase, and may indicate the underlying mechanism in this treatment strategy. Trial registration: This study was registered with the Chinese Clinical Trial Registration (registration number: ChiCTR-INR-16010075) on December 4, 2016. Study protocol refers to 1.0. Patient recruitment began in December 2016 and will be ended in November 2019.

Acute ischemic stroke (AIS) is a major cause of adult disability (Catanese et al., 2017; Rabinstein, 2017; Sun et al., 2017). Early diagnosis and intervention is considered an important measure in preventing long-term disability after AIS (Ly and Maquet, 2018; Yin and Wang, 2018). Current standard methods for early treatment of AIS include fibrinolytic therapy (Phan et al., 2016) and antiplatelet therapy (Yin and Wang, 2018). However, few patients with AIS receive fibrinolytic therapy within 3–4.5 hours after disease onset (Cheng and Kim, 2015; Yan et al., 2015), and there is evidence that antiplatelet therapy does not lower the risk for recurrent stroke, but can instead increase the risk for hemorrhage (Bakheet et al., 2015).

Traditional Chinese medicine is the most widely used method to treat AIS in Chinese and Central Asian Chinese communities (Venketasubramanian et al., 2009, 2013; Young et al., 2010; Chen et al., 2013; Wan et al., 2015; Du et al., 2016; Zhang et al., 2016). Given the limitations of standard therapies, researchers are increasingly interested in the use of traditional Chinese medicine to treat this condition (Chang et al., 2016). According to traditional Chinese medicine theory, the syndrome is the overall reaction of the body’s pathophysiological state. AIS has been shown to be caused by three pathogens, “wind,” “fire,” and “phlegm” (Song et al., 2009), and the elimination of these pathogenic factors may alleviate the symptoms of stroke.

Although traditional Chinese medicine and western medicine have been widely used for treatment of AIS in clinical settings (Chen et al., 2013; Wan et al., 2015; Du et al., 2016) [Table 1], the objective efficacy of traditional Chinese medicine combined with western medicine requires further investigation.

Dongfang Hospital, Beijing University of Chinese Medicine is a grade 3 class-A traditional Chinese medicine hospital, and has previously participated in a number of key traditional Chinese medicine projects funded by the National Population and Family Planning Commission and Ministry of Health of China. Each investigator within the study team is educated to master’s degree level or higher, has a professional title of associate chief physician or higher, and has more than 5 years of clinical experience in neurology.

Study population

Recruitment

Patients with AIS will receive treatment at the emergency department because of their unstable disease condition. Therefore, the study population will be screened for eligibility and recruited from the Department of Emergency, Dongfang Hospital, Beijing University of Traditional Chinese Medicine. Demographic data for each patient, including sex, age, body mass, body weight, and medical history, will be collected on a case report form upon admission.

Eligibility

Inclusion criteria

Patients who are scheduled to receive treatment will be considered for inclusion if they meet the following criteria: a) fulfillment of the diagnostic criteria for AIS as per the 2014 Chinese Guidelines on the Diagnosis and Treatment of Acute Ischemic Stroke (Chinese Society of Neurology and Chinese Society of Neurology Cerebrovascular Disease Section, 2015); b) National Institute of Health Stroke Scale (NIHSS) score of 5–20; c) stroke onset time ≤ 72 hours; d) men and women > 40 years of age; e) provision of written informed consent from participants, or from the legal guardians of patients who are unconscious.

Patients presenting with one or more of the following criteria will be withdrawn from the study: a) Allergy to the study drug; b) concomitant use of other treatments or drugs that may enhance the efficacy of the investigational products; c) worsening condition, serious complications, or serious adverse events. The detailed reasons for withdrawal will be recorded in the case report forms.

Patients that experience serious adverse events or die following an adverse drug reaction will be financially compensated by an insurance company. Serious adverse events refer to adverse drug reactions that occur during the duration of the clinical trial and result in hospitalization, prolonged hospital stay, disability, or decreased work capacity; are life-threatening; or result in death.

Interventions

Grouping

Patients will be randomly divided into one of two groups: a traditional Chinese medicine + western medicine group (com-bined treatment group) and a control group. Immediately after admission, all patients will receive 3-day early treatment for AIS.

National Institute of Health Stroke Scale (NIHSS) score on days 1, 3, 7, and 14 after treatment. The NIHSS is used to evaluate neurological deficits, including level of consciousness, cognitive function, sensory function, visual field test, and reflex, and has been widely used for evaluating neurological deficits in patients with AIS (Kwah and Diong, 2014).

Traditional Chinese medicine stroke scale score on days 1, 3, 7, and 14 after treatment. This scale is used to evaluate the severity of neurological deficits based on the severity of traditional Chinese medicine syndromes (Gao et al., 2011).

Secondary outcome measures

Barthel index on days 1, 3, 7, and 14 after treatment. Barthel index can reflect the severity of stroke (Quinn et al., 2011).

Modified Rankin scale score on days 1, 3, 7, and 14 after treatment. The Modified Rankin scale is used to reflect the severity of stroke (Bruno et al., 2013).

Glasgow coma scale score before treatment and on days 1, 3, 7, and 14 after treatment. The Glasgow coma scale is used to evaluate patient consciousness (Teasdale and Jennett, 1974).

Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels before treatment and on day 3 after treatment. Previous studies have shown that these factors are associated with infarct volume and clinical prognosis in patients with AIS (Abdelnaseer et al., 2017; Geiseler and Morland, 2018).

Adverse events

To ensure patient safety, routine blood and urine testing, routine stool analysis, liver and kidney function, coagulation function, D-dimer level, and electrocardiogram assessment will be performed after treatment. Key indicators will be monitored throughout the trial.

The onset time, symptoms and signs, duration, severity, treatment measures, treatment efficacy, and causal relationship of any adverse events occurring during the 3-day treatment period and the 2-week follow-up period will be recorded. Serious adverse events will be reported in the case report forms and promptly to the institutional ethics committee.

Timing of outcome measure evaluation and adverse events is shown in [Table 2].

With reference to a previous study (Zeng and Zhao, 2016), we assumed an NIHSS score for the combined treatment and control groups of 9.49 ± 4.98 and 12.32 ± 4.43 points, respectively. Taking α = 0.05 and β = 0.1, an effective sample size of n = 53/group was calculated according to superiority and non-inferiority design formulae. Assuming a withdrawal rate of 10%, a final sample size of n = 60/group will be used. Therefore, a total of 120 patients (60 patients in each group) will be included in this study.

Randomization

Designated researchers will generate a random digital sequence using Excel 2007 software (Microsoft Corporation, Redmond, WA, USA), and sequence numbers will be printed onto digital cards and sealed in opaque envelopes printed with a serial number corresponding to the random digital sequence numbers. Eligible patients who have provided written informed consent will be randomized to the combined treatment group (n = 60) or the control group (n = 60) according to the assigned digital sequence.

Blinding

It is difficult to perform blinding to investigators and participants, so only assessors will be blinded to grouping.

Ethical approval

This study will be performed in accordance with the Declaration of Helsinki developed by the World Medical Association. This study was approved by Hospital Ethics Committee, Dongfang Hospital, Beijing University of Chinese Medicine (approval No. JDF-IRB-2016033602) on November 2, 2016 (Additional file 1[Additional file 1]). The whole study process will be supervised by the research committee. Any severe adverse events will be reported to the research committee immediately. Changes to the study design can only be made with the permission of the research committee.

Informed consent

It is the responsibility of the investigators to provide the patient or his or her legal guardian with a complete and comprehensive introduction about the purpose, procedure, and possible benefits and risks of this study. Each patient or his or her legal guardian will sign the informed consent (Additional file 2[Additional file 2]) and he or she will understand that they have the right to withdraw from the study at any time. The participant’s personal privacy and data confidentiality will be protected during the study period. The manuscript was prepared in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statements (Additional file 3[Additional file 3]). Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.

Statistical analysis

SPSS 20.0 software (IBM Corp., Armonk, NY, USA) will be used for data analysis. Continuous variables are expressed as the mean ± SD. Categorical variables are expressed as frequency or percentage. The t-test (if normally distributed) or nonparametric test (if abnormally distributed) will be used for comparison of continuous variables between groups. The chi-square test or nonparametric test will be used for comparison of categorical variables between groups. A level of P < 0.05 will be considered statistically significant. Efficacy will be analyzed according to the intention-to-treat principle. Missing values will be imputed by the last observation carried forward method.

Data collection

All data will be recorded in case report forms by trained investigators. To ensure data reality, all investigators participating in this trial will receive training regarding how to fill in case report form prior to initiation of this trial. All data will be collected on site and input in real-time using a double data entry strategy with Epi-Data 3.0 data management software.

Data management

After data entry, real-time quality control and online error correction will be performed by investigators responsible for data entry using a two-pass verification method. The missing data or special errors will be detected by the software program and resolved by the investigators. Transparency in the research process should be ensured, the research progress and the existing problems should be managed at any time and rationally solved under the permission of protocol principle.

Quality control

Before the study protocol put into practice, a series of training sessions will be performed to ensure that all the investigators have a full understanding of the study protocol and mastery of the standard operating procedures. The case report forms will be regularly checked by the supervisors, and the investigators will be notified of any problems in a timely manner. The members of research team will meet regularly to discuss problems that they have confronted and share their experience with others. Moreover, a telephone will be established for the participants who have been discharged. Patients enrolled in the clinical trial will be able to receive a certain amount of traditional Chinese medicine for combined treatment group and some related examination subsidies for both groups.

Audits

The clinical monitors will be the persons who come from the department of neurology but do not participate in this study and be responsible for reviewing trial data, extracting medical records, visiting the trial site, and inquiring about relevant personnel once every 6 months during the study period. The clinical monitors will report the progression of the trial to the Medical Ethics Committee. Trial registration will be updated simultaneously.

Confidentiality

All electronic data will be password-protected.

Results dissemination

Results will be available at ResMan Research Manager (http://www.medresman.org/) within 6 months after the completion of the trial without any charge and disseminated by publication through publication in a peer-reviewed journal.

Discussion

Study limitations

This study will not evaluate the long-term efficacy of traditional Chinese medicine combined with western medicine in the treatment of AIS, and the study will be conducted at a one center only.

Treatment applicability

Traditional Chinese medicine has been widely used in China for the treatment of AIS (Zhang et al., 2016), although most studies examining combination treatment with traditional Chinese medicine and western medicine focus only on the effects of the specific drugs (Venketasubramanian et al., 2009, 2013; Young et al., 2010; Chen et al., 2013; Venketasubramanian et al., 2013; Wan et al., 2015; Du et al., 2016; Zhang et al., 2016). To date, few studies have reported the efficacy of traditional Chinese medicine combined with western medicine in the early phase of AIS.

This study will be the first to investigate the efficacy and safety of traditional Chinese medicine combined with western medicine for the treatment of AIS based on the primary syndrome elements of traditional Chinese medicine theory.

Interpretation

Traditional Chinese medicine has been widely used for the clinical treatment of acute ischemic stroke in China (Zhang et al., 2016). Gastrodin injection (Yu et al., 2007), Tanreqing injection (He, 2007), and Xingnaojing injection (Peng et al., 2014) are described in the Chinese Pharmacopoeia for the clinical treatment of AIS via an intravenous administration routes. In this study, oral stroke initial state decoction will be administered alongside intravenous Gastrodin injection and Tanreqing injection. This study will investigate the efficacy and safety of 3-day comprehensive intensive therapy by assessing neurological deficits, traditional Chinese medicine stroke scale score, quality of life in patients with acute ischemic stroke. Results of this study will provide evidence for the use of traditional Chinese medicine in combination with western medicine for the treatment of AIS.

This work was supported by the National Special Scientific Research Project for the Construction of Traditional Chinese Medicine Clinical Research, No. JDZX2015289; the Central University Basic Scientific Research Foundation of China, No. 2016-JYB-JSPY-047. The funders had no role in the study design, data collection, management, analysis, and interpretation; paper writing; or decision to submit the manuscript for publication.

Institutional review board statement

All experimental procedures will be performed in strict accordance with the Declaration of Helsinki and relevant ethical requirement of the Dong Fang Hospital, Beijing University of Chinese Medicine, China (approval No. JDF-IRB-2016033602) on November 2, 2016.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms from the patients or their legal guardians. In the forms, the patients or their legal guardians will give their consent for patients’ images and other clinical information to be reported in the journal. The patients or their legal guardians understand that the patients’ names and initials will not be published and due efforts will be made to conceal the patients’ identity.

The statistical methods of this study were reviewed by the biostatistician of the Dongfang Hospital, Beijing University of Chinese Medicine, China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this manuscript, after deidentification (text, tables, figures, and appendices) will be available indefinitely at ResMan Research Manager () within 6 months after the completion of the trial without any charge. Other raw data can be achieved through contact with the corresponding author. Results will be disseminated by publication in a peer-reviewed journal.

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